1. Field of Invention
This invention relates to indolines and more particularly to 3,3-heterocyclic-disubstituted indolines, pharmaceutical compositions containing them, processes for preparing them and methods of using them in mammals to treat cognitive deficiencies and/or neurological function deficits and/or mood disturbances such as found, for example, in degenerative nervous system diseases.
2. Background Including Prior Art
There is a steadily growing need for effective treatment for Nervous System Disorders causing cognitive and neurological deficiencies. Many of these diseases, of which the incidence generally rises with increasing age, are due to degenerative changes in the nervous system. Although in early stages of some diseases certain systems are rather specifically affected (e.g. cholinergic systems in Alzheimer's Disease, and Myasthenia Gravis, the dopaminergic system in Parkinson's Disease, etc.), multiple neurotransmitter system deficiencies (acetylcholine, dopamine, norepinephrine, serotonin) are generally found at later stages of these diseases and are thought to exist at all stages of diseases such as senile dementia, multi-infarct dementia, Huntington's disease, mental retardation, etc. This may explain the generally observed multiple symptomatology which includes cognitive, neurological and affective/psychotic components (see Gottfries, Psychopharmacol. 86, 245, 1985). Deficits in the synthesis and release of acetylcholine in the brain are generally thought to be related to cognitive impairment (see Francis et al., New England J. Med., 313, 7, 1985) whereas neurological deficits (e.g., Parkinson Symptoms) and mood/mental changes may be related to impairment of dopaminergic and serotonergic systems, respectively. Other neurological deficits (e.g., Myasthenia Gravis) are related to cholinergic deficiencies in the peripheral nervous system.
Treatment strategies employed hitherto encompass vasoactive drugs like vincamine and pentoxifylline; "metabolic enhancers" like ergoloid mesylates, piracetam and naftidrofuryl; neurotransmitter precursors like 1-DOPA, choline and 5-hydroxytryptamine; transmitter metabolizing enzyme inhibitors like physostigmine; and neuropeptides like adrenocorticotropic hormone and vasopressin-related peptides. Except for 1-DOPA treatment in Parkinson's disease and cholinesterase inhibitor treatment in Myasthenia Gravis, these treatment strategies have generally failed to produce clinically significant improvements (Hollister, Drugs, 29, 483, 1985). Another strategy to treat these multiple symptoms is to enhance the residual function of the affected systems by enhancing the stimulus-induced release of neurotransmitters. Theoretically, such an enhancement would improve the signal-to-noise ratio during chemical transmission of information, thereby reducing deficits in processes related to cognition, neurological function and mood regulation.
To date, there are not many patent or literature references which describe 3,3-heterocyclic disubstituted indolines. Most pertinent, are Japanese Patent No. 55-129284, issued Oct. 6, 1980 and M. Ogata et al., Eur. J. Med. Chem-Chim. Ther., 16(4), 373-378 (1981), which describe antifungal compounds having the formula: ##STR3## wherein R is H, halogen, alkyl, or alkoxy;
R.sup.1 is H, alkyl, aryl or acyl; and PA0 R.sup.2 is thienyl, or imidazole, amongst non-heterocyclic groups. PA0 R.sub.3 is H or alkyl. PA0 Z is O or S; PA0 R is C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.8 cycloalkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or ##STR6## V, W, X, and Y independently are H, halo, C.sub.1 -C.sub.3 alkyl, OR.sup.1, NO.sub.2, CF.sub.3, CN or NR.sup.1 R.sup.2 ; PA0 R.sup.1 and R.sup.2 independently are H or C.sub.1 -C.sub.3 alkyl; PA0 -- .circle.H and -- .circle.H' independently are 6-membered heterocyclic rings containing at least one nitrogen atom as a part of the ring optionally substituted with one substituent selected from the group C.sub.1 -C.sub.3 alkyl, halo, OR.sup.1 or NR.sup.1 R.sup.2 ; or PA0 (a) contacting an oxindole of the formula ##STR7## wherein p, X, Y, and R are as defined above, with a base; (b) contacting the product of step (a) with a compound of the formula D--CH.sub.2 -- .circle.H wherein -- .circle.H is as defined above and D is a halide, methanesulfonate, or p-toluenesulfonate; PA0 (c) contacting the product of step (b) with a compound of the formula D--CH.sub.2 -- .circle.H' wherein -- .circle.H' is defined above and D is a halide, methanesulfonate, or p-toluenesulfonate; and PA0 (d) optionally contacting the product of step (c) with Lawesson's reagent or with P.sub.4 S.sub.10 to prepare the thiooxindole. PA0 p is 0; or PA0 Z is O; or PA0 X and Y are H; or PA0 R is CH.sub.3, phenyl or m-chlorophenyl; or PA0 --.circle.H and -- .circle.H' are each pyridyl attached by a ring carbon atom. PA0 3,3-Bis(2-pyridylmethyl)-1-phenylindolin-2-one; PA0 3,3-Bis(3-pyridylmethyl)-1-phenylindolin-2-one; PA0 3,3-Bis(4-pyridylmethyl)-1-phenylindolin-2-one; PA0 3,3-Bis(4-pyridylmethyl)-1-methylindolin-2-one; PA0 3,3-Bis(4-pyridylmethyl)-1-(3-chlorophenyl)indolin-2-one;
R. W. Daisley, et al., J. Heterocyclic Chem., 19, 1913-1016, (1982), report 1-methyl-3,3-dipiperidinoindol-2-(3H)-one as product from the reaction of the corresponding (Z) or (E) 2-arylmethylidene-indol-3(2H)-one with ethyl cyanoacetate in the presence of excess piperidine. No utility for the compound is described.
Japanese Patent No. 59-98896 describes high sensitivity, high stability recording medium containing a 3,3-disubstituted-2-oxo-2,3-dihydroindole derivative of the formula shown below as a near infrared absorber. ##STR4## wherein R.sub.1, R.sub.2, same or different, are a saturated heterocyclic ring including morpholino, pyrrolidinyl, amongst others containing at least one nitrogen atom; and
3,3-bis(morpholino)oxoindole is also disclosed in U.S. Pat. No. 4,273,860, to A. Adin, June 16, 1981 and in A. Adin, et al., Research Disclosures, 184, 446-454 (1979), as a destabilizer material in a photoinhibitor composition utilizing cobalt (111) complexes.
The above references, other than J55-129284, and M. Ogata et al., Eur. J. Med. Chem-Chim. Ther., 16(4), 373-378 (1981) all describe 3,3-disubstituted indolones wherein the heterocyclic groups are both saturated rings. In all of the above references, the heterocyclic ring is attached to the indoline by a ring nitrogen. Furthermore in the references other than J55-129284, there is no suggestion of pharmaceutical utility for these 3,3-disubstituted indolines.